Recent evidence suggests that mutations in RNA splicing genes occur in a variety of human cancers. These mutations are particularly prevalent in hematopoietic malignancies such as acute myeloid leukemia (AML) (Hahn and Scott, Nat Genetics 2012; Yoshida et al., Nature 2011), which arises de novo or secondary to myeloproliferative neoplasms (MPNs) or myelodysplastic syndromes (MDS). However, the role of RNA splicing alterations and targeted modulation of splicing activity in maintenance of leukemia stem cells (LSC), which contribute to disease relapse and drug resistance, has been unclear. To address these questions, we performed comparative splice isoform profiling of FACS-purified hematopoietic progenitors from secondary AML (sAML) and normal bone marrow. We then investigated the LSC inhibitory efficacy of a stable and potent splicing modulatory agent, 17S-FD-895.
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